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-Blockers" Provide Evidence for Two Agonist Activation Sites or Conformations of the Human 1-Adrenoceptor
Institute of Cell Signalling, Medical School, Queen's Medical Centre, Nottingham, United Kingdom
Previous work with
4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one
(CGP 12177) has led to the suggestion that there are two different agonist
conformations of the human 
1-adrenoceptor: 1) where classic
agonists (catecholamines) and -antagonists act, and 2) where CGP 12177
is an agonist and relatively resistant to inhibition by -adrenoceptor
antagonists. In the present study, we have used studies of cAMP response
element-regulated gene transcription to confirm the presence of these two
1-adrenoceptor sites/conformations and to provide strong
evidence that a range of clinically used -adrenoceptor blockers
(-blockers) exhibit differential agonists and/or antagonist actions at
the two sites.
[2-(3-Carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulphonate
(CGP 20712A) and atenolol act as classic antagonists at the catecholamine
binding site but have much lower affinity for the secondary CGP 12177 site.
CGP 12177 and carvedilol are potent antagonists at the catecholamine site but
mediate substantial agonist actions on gene transcription via the secondary
antagonist-resistant site at higher concentrations. Agonist effects of
-blockers are not, however, confined to this secondary site, and we show
that some (particularly acebutolol and labetolol) act primarily via the
catecholamine site, whereas others (pindolol and alprenolol) can stimulate
both. The different responses to -blockers seen in the clinic may
therefore be caused in part by these -blocker agonist responses and the
differential activation of the two sites or conformations.
Address correspondence to: Professor S. J. Hill, Institute of Cell Signaling, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: stephen.hill{at}nottingham.ac.uk
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